TY - JOUR
T1 - Nigral GFRα1 infusion in aged rats increases locomotor activity, nigral tyrosine hydroxylase, and dopamine content in synchronicity
AU - Pruett, Brandon S.
AU - Salvatore, Michael F.
N1 - Funding Information:
Acknowledgments This work was funded in part by an NIH grant award to MFS, 1R01AG040261-01A1, and The Ike Muslow Predoctoral Fellowship to BSP. The authors also wish to thank Victoria Fields and Charles Dempsey for outstanding technical support.
PY - 2013/6
Y1 - 2013/6
N2 - Delivery of exogenous glial cell line-derived neu-rotrophic factor (GDNF) increases locomotor activity in rodent models of aging and Parkinson's disease in conjunction with increased dopamine (DA) tissue content in sub-stantia nigra (SN). Striatal GDNF infusion also increases expression of GDNF's cognate receptor, GFRα1, and tyro-sine hydroxylase (TH) ser31 phosphorylation in the SN of aged rats long after elevated GDNF is no longer detectable. In aging, expression of soluble GFRα1 in the SN decreases in association with decreased TH expression, TH ser31 phosphorylation, DA tissue content, and locomotor activity. Thus, we hypothesized that, in aged rats, replenishing soluble GFRα1 in SN could reverse these deficits and increase locomotor activity. We determined that the quantity of soluble GFRα1 in young adult rat SN is ∼3.6 ng. To replenish age-related loss, which is ∼30 %, we infused 1 ng soluble GFRα1 bilaterally into SN of aged male rats and observed increased locomotor activity compared to vehicle-infused rats up to 4 days following infusion, with maximal effects on day 3. Five days after infusion, however, neither locomotor activity nor nigrostriatal neurochemical measures were significantly different between groups. In a separate cohort of male rats, nigral, but not striatal, DA, TH, and TH ser31 phosphorylation were increased 3 days following unilateral infusion of 1 ng soluble GFRα1 into SN. Therefore, in aged male rats, the transient increase in locomotor activity induced by replenishing age-related loss of soluble GFRα1 is temporally matched with increased nigral dopaminergic function. Thus, expression of soluble GFRα1 in SN may be a key component in locomotor activity regulation through its influence over TH regulation and DA biosynthesis.
AB - Delivery of exogenous glial cell line-derived neu-rotrophic factor (GDNF) increases locomotor activity in rodent models of aging and Parkinson's disease in conjunction with increased dopamine (DA) tissue content in sub-stantia nigra (SN). Striatal GDNF infusion also increases expression of GDNF's cognate receptor, GFRα1, and tyro-sine hydroxylase (TH) ser31 phosphorylation in the SN of aged rats long after elevated GDNF is no longer detectable. In aging, expression of soluble GFRα1 in the SN decreases in association with decreased TH expression, TH ser31 phosphorylation, DA tissue content, and locomotor activity. Thus, we hypothesized that, in aged rats, replenishing soluble GFRα1 in SN could reverse these deficits and increase locomotor activity. We determined that the quantity of soluble GFRα1 in young adult rat SN is ∼3.6 ng. To replenish age-related loss, which is ∼30 %, we infused 1 ng soluble GFRα1 bilaterally into SN of aged male rats and observed increased locomotor activity compared to vehicle-infused rats up to 4 days following infusion, with maximal effects on day 3. Five days after infusion, however, neither locomotor activity nor nigrostriatal neurochemical measures were significantly different between groups. In a separate cohort of male rats, nigral, but not striatal, DA, TH, and TH ser31 phosphorylation were increased 3 days following unilateral infusion of 1 ng soluble GFRα1 into SN. Therefore, in aged male rats, the transient increase in locomotor activity induced by replenishing age-related loss of soluble GFRα1 is temporally matched with increased nigral dopaminergic function. Thus, expression of soluble GFRα1 in SN may be a key component in locomotor activity regulation through its influence over TH regulation and DA biosynthesis.
KW - Aging
KW - Bradykinesia
KW - Dopamine
KW - GFRα1
KW - Parkinsonism
KW - Striatum
KW - Substantia nigra
KW - Tyrosine hydroxylase
UR - http://www.scopus.com/inward/record.url?scp=84887313840&partnerID=8YFLogxK
U2 - 10.1007/s12035-013-8397-7
DO - 10.1007/s12035-013-8397-7
M3 - Article
C2 - 23321789
AN - SCOPUS:84887313840
SN - 0893-7648
VL - 47
SP - 988
EP - 999
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 3
ER -